Effect of Initiation With Sacubitril/valsartan on Blood Neurodegeneration Markers in HFrEF

BACKGROUND: Sacubitril/valsartan is a key therapy for heart failure with reduced ejection fraction (HFrEF). However, concerns remain regarding its potential impact on cognitive function, because neprilysin inhibition may influence amyloid-β (Aβ) metabolism. This study evaluates the effect of sacubitril/valsartan on plasma biomarkers of neurodegeneration. METHODS: Plasma neuromarkers (i.e., Aβ40, Aβ42, neurofilament light chain [NfL], and total tau [t-tau]) were measured at baseline, 3 months and 1 year after sacubitril/valsartan initiation by using the single-molecule array (SIMOA) technology in a cohort with HFrEF from a prospective registry with Biobank. Comparisons were made for baseline vs 3-month and baseline vs 1-year follow-up. RESULTS: A total of 31 patients with HFrEF (median age: 61 years, 74% male, median NT-proBNP level: 2333 pg/mL) were included. Aβ40 increased transiently at 3 months (228.6 pg/mL [Q1-Q3: 157.8-321.1] vs 138.8 [110.0-202.2]; P < 0.001) but remained unchanged at 1 year (215.0 [106.5-290.9]; P = 0.052). Aβ42 remained stable (9.90 [6.67-12.49] and 8.43 [5.57-11.86] vs 7.84 [6.50-11.02] pg/mL; P = 0.108 and 0.771), resulting in a reduced Aβ42/Aβ40 ratio at both follow-ups (0.039 [0.036-0.049] at 3 months, P < 0.001; 0.048 [0.041-0.060] at 1 year, P = 0.026; vs 0.055 [0.052-0.061]). Total tau remained unchanged (1.13 [0.91-1.90] and 1.21 [0.85-1.65] vs 1.03 [0.82-1.53] pg/mL; P = 0.068 and 0.188), while NfL increased at 1 year (28.3 [16.5-78.6] vs 22.6 [15.1-46.9] pg/mL; P = 0.013), with no short-term change (25.3 [15.0-51.3]; P = 0.502). CONCLUSION: Sacubitril/valsartan therapy in patients with HFrEF leads to a transient increase in Aβ40 and a sustained reduction in the Aβ42/Aβ40 ratio. Stable t-tau and short-term stable NfL levels provide reassurance regarding the absence of immediate neuronal injury, while an NfL increase observed at 1 year may indicate ongoing progression of heart failure rather than direct neurotoxicity. These findings highlight the need for cautious interpretation of the Aβ42/Aβ40 ratio in neurocognitive assessments among patients treated with angiotensin receptor-neprilysin inhibitors. Further studies are warranted to clarify the long-term cognitive implications of sacubitril/valsartan in patients with HFrEF.